Effective and scalable mechanochemical synthesis of platinum(II) heteroleptic anticancer complexes

Abstract

With global cancer cases and their associated costs steadily increasing, there is an imperative for sustained research efforts to improve health outcomes and mitigate its socio-economic impact. Several treatments have been developed over the last few decades to alleviate these issues. Among them, platinum(II) and(IV)(Pt(II) and(IV)) heteroleptic complexes show promise in the field of cancer treatment. However, the design of innovative derivatives towards enhanced cancer therapies is hindered by the limited number of synthetic methods currently available. Mechanochemistry is rapidly emerging as a powerful alternative to traditional synthetic routes. In this context, it not only offers a fast, efficient and scalable synthesis with a reduced environmental footprint but also renders a new conceptual synthetic framework in materials science and pharmaceuticals. Herein, we demonstrate proof-of-concept that Pt(II) heteroleptic complexes can be readily synthesised using a solvent-free milling and kneading mechanochemical method. Using PHENSS as an example, the synthesis was readily scaled up by 6.7-fold, whilst maintaining high yield and purity. The newly developed method significantly reduced reaction time by 8-fold and energy consumption by 28.8-fold, in comparison to the traditional route. Further, the environmental footprint was notably reduced when mechanochemistry was employed (i.e., ∼700-fold reduction in the environmental factor (E-factor) and ∼200-fold in the process mass intensity (PMI)). This work also determined that the mechanochemical method did not alter the in vitro growth inhibition activity. This study provides new insights into the mechanochemical synthesis of six Pt(II) heteroleptic complexes: PHENSS, 56MESS, 47MESS, 4MESS, 3478MESS and 5ClSS, and sets the foundation for scalable and sustainable routes towards heteroleptic metal complexes with potential applications across diverse fields.

---

Green foundation

1. An unprecedented milling and kneading approach was developed to synthesise platinum heteroleptic anticancer complexes. These complexes have not previously been accessed via a green approach. This unique approach significantly reduced water consumption compared to the incumbent methodology. Energy consumption and reaction waste were also notably reduced, aligning with the 12 principles of green chemistry.

2. Green metrics quantified our green chemistry achievement. The mechanochemical process reduced the E-factor (∼700-fold) and PMI (∼200-fold) by simply eliminating the use of water. Energy consumption was also cut by 28.8-fold, driven in part by an 8-fold reduction in reaction time.

3. To enhance the RME and AE values of the developed method, future work will optimise mechanochemical stoichiometry. Mechanochemical synthesis of the precursor [Pt(S,S-DACH)Cl₂] will be explored to achieve a completely solvent-free process and assess greener alternatives to THF for purification.

Introduction

The global impact of cancer has both direct and indirect consequences on society. According to the latest GLOBOCAN database from the International Agency for Research on Cancer (IARC), there were 18.7 million new cases and 9.7 million deaths in 2022.¹ By 2050, the incidence of cancer is projected to rise to 35 million globally. This increase directly impacts societal well-being and increases the direct cost of cancer to ∼US$25.5 trillion by 2050.² Indirectly, the loss of productivity due to cancer further burdens the global economy. To save lives as well as preserve societal well-being and the economy's productivity, efforts in cancer research must evolve.

Metal coordination complexes are a broad class of complexes with significant potential in catalysis, industry, and pharmaceuticals. For instance, transition metal-containing species like platinum(II) and(IV) (Pt(II) and(IV)) heteroleptic complexes have shown promise in optoelectronic materials, stimuli-responsive systems, sensors, photocatalysis, and detection technologies.^3,4 Beyond catalysis and sensing applications, Pt(II) and(IV) complexes like cisplatin, carboplatin, and more recently, PHENSS and 56MESS have demonstrated excellent anticancer activity.^5–8 Although conventional complexes like cisplatin have successfully treated several cancers for over four decades, their application is limited by clinical drawbacks.⁹ Non-conventional Pt(II) and(IV) derivatives like PHENSS and 56MESS aim to address these issues, but they face major synthetic challenges pertaining to efficiency, scalability and sustainability. This highlights the need for a better synthetic approach for Pt(II) and(IV) heteroleptic complexes.

Non-conventional Pt(II)-based scaffolds are currently achieved using inefficient and tedious methods. These complexes are synthesised by reflux for at least 24 h, generally using reaction scales of 0.1–1 g.¹⁰ Exceeding this range increases reaction time and compromises product yield, making this method impractical for scaling up. Additionally, C18 Sep-Pak column is used to purify the desired product, which is time-consuming and leads to excessive solvent consumption.

Improving the synthesis of non-conventional Pt(II) complexes is essential as they can not only be used as antineoplastic agents but also be valuable precursors to promising bioactive complexes. For instance, multiple studies have oxidised Pt(II) PHENSS and 56MESS species to their Pt(IV) counterparts, enabling further chemical modifications to enhance their solubility, selectivity or biological activity.^11–13 However, accessing these species in preparative scales remains challenging.¹⁴ To streamline this process, synthetic optimisation of these Pt(II) precursors is essential.

Mechanochemistry is rapidly emerging as a powerful method for driving solid-state reactions, offering reduced solvent use, shorter reaction times, and improved reaction kinetics and product selectivity.^15–17 This synthetic approach effectively overcomes the limitations of traditional methods while providing a scalable and environmentally sustainable synthesis for both organic and inorganic fields, including metal complex syntheses.^17–28 In the context of mechanically synthesised Pt(II) and(IV) complexes, a few examples comprising different ligands (i.e., N-heterocyclic carbene and sodium β-diketonate ligands) have been previously demonstrated, including Pt(II) assemblies for guanine quadruplex targeting.^29–32

However, the direct mechanochemical synthesis of biologically relevant anticancer-based heteroleptic Pt(II) complexes (i.e., cisplatin-type derivatives) remains unexplored. These biologically relevant complexes generally require harsh reaction conditions and tedious purification steps.

Herein, we report a mechanochemical method developed for six non-conventional Pt(II) complexes bearing S,S-diaminocyclohexane (S,S-DACH) and phenanthroline-based ligands as denoted in Scheme 1. The species produced, [Pt(P_L)(A_L)]²⁺, where P_L is 1,10-phenanthroline (Phen); 5,6-dimethyl-1,10-phenanthroline (56Me₂Phen); 4,7-dimethyl-1,10-phenanthroline (47Me₂Phen); 4-methyl-1,10-phenanthroline (4MePhen); 3,4,7,8-tetramethyl-1,10-phenanthroline (3478Me₄Phen) or 5-chloro-1,10-phenanthroline (5ClPhen), and A_L is S,S-DACH to form PHENSS, 56MESS, 47MESS, 4MESS, 3478MESS and 5ClSS, respectively, have been obtained via an unconventional milling and kneading approach. This approach produces the target compounds in high yields via a fast and scalable ball-milling route. In addition, their cytotoxicity was also assessed to determine if the in vitro activity was altered due to mechanochemistry. Furthermore, the newly established mechanochemical protocol has been assessed against the conventional solution-based protocol using various green metric calculations. Our research offers a practical methodology for large-scale Pt(II) complex synthesis and a conceptual framework for reduced and/or solvent-free production of other relevant heteroleptic systems in materials science and drug development.

Scheme 1 Schematic diagram of PHENSS mechanochemical vs. in-solution syntheses.

Results and discussion

Mechanochemical synthesis of [Pt(S,S-DACH)(P_L)]Cl₂

Traditionally, [Pt(P_L)(A_L)]²⁺ complexes are synthesised by refluxing [Pt(S,S-DACH)Cl₂] with 1.05 mol. equiv. of the chosen phenanthroline derivative in H₂O for 24 h or longer. The solution is then reduced in vacuo to about 8% volume, syringe filtered and purified through a C18 Sep-Pak column.¹⁰ This method is time-consuming, solvent-intensive and challenging to scale up, with typical reactions limited to 1 g of [Pt(S,S-DACH)Cl₂] to avoid reduction in yields.

With this in mind, we set off using the current solution-based methodology as a guide for reaction quantities, 1.05 mol. equiv. of P_L was milled with [Pt(S,S-DACH)Cl₂]. Unfortunately, these attempts to produce the targeted Pt(II) complexes failed, as evidenced by HPLC and ¹⁹⁵Pt NMR. Our attempts were unsuccessful, even with extended milling and Liquid Assisted Grinding (LAG) using various solvents. Heat (70 °C) was also applied to the stainless-steel reaction vessels; however, this attempt did not yield the targeted product either. Preliminary trials, conducted with Phen and 56Me₂Phen, indicated that the direct translation of the solution-based synthetic route, rather than the P_L, was the limiting factor.

To address the shortcomings of the initial attempts, the order of ligand coordination conventionally used in solution was reversed, whereby [Pt(P_L)Cl₂] was milled with the A_LS,S-DACH. To our delight, the order reversal, compared to solution protocols, produced the desired product (Fig. 1), signifying the importance of coordination order and the possible effects of steric hindrance and/or solid-state intramolecular interactions in the reaction outcome.^33,34 Moreover, S,S-DACH liquid state at room temperature may have also facilitated product formation.¹⁹ The Pt(II) starting materials used throughout our studies [Pt(Phen)Cl₂], [Pt(56Me₂Phen)Cl₂], [Pt(47Me₂Phen)Cl₂], [Pt(4MePhen)Cl₂], [Pt(3478Me₄Phen)Cl₂] and [Pt(5ClPhen)Cl₂] had been previously synthesised following the published method³⁵ and these available stocks were repurposed for this work. Also, the precursor [Pt(Phen)Cl₂] was the selected specie for method optimisation due to the comprehensive literature references available and cost efficiency.

Fig. 1 Reverse-phase HPLC chromatogram of the PHENSS experiment using 1 mol. equiv. of S,S-DACH added to [Pt(Phen)Cl₂] post 4 h of milling with detection set to 254 nm. Inset: PHENSS and [Pt(Phen)Cl₂] chemical structures as well as 1D ¹⁹⁵Pt NMR of the reaction mixture, demonstrating the successful coordination of precursors.

The iterative optimisation of PHENSS synthesis involved refining both reaction time and the number of S,S-DACH mol. equiv. used to achieve full conversion. Initial trials using 1 mol. equiv. of S,S-DACH with [Pt(Phen)Cl₂] yielded a product peak area of 70% after 4 h of milling, as monitored by HPLC. The solubility of the reaction, a critical parameter for monitoring the reaction outcome, improved only marginally with extended milling. Incremental additions of S,S-DACH ligand (0.5 mol. equiv. per h) were subsequently performed, progressively enhancing solubility and increasing product peak area to 97%.

Further experiments determined that excess S,S-DACH is indeed required to drive the PHENSS reaction to completion. However, since the necessity of gradual addition to achieve high conversions was unclear, we comparatively studied the effect of single and gradual additions of S,S-DACH at varying reaction times (see Table 1).

Table 1 Method optimisation of PHENSS mechanochemistry synthesis without solvent

Exp.	S,S-DACH mol. equiv.	Time S,S-DACH added (min)	Manual kneading	Reaction time (h)	Yield (%)
1	2	0	No	5	74
2	2	0 and 60	No	5	64
3	2	0 and 99	Yes	3	89
4	2	0	Yes	3	69

---

While yields were similar in the case of single addition (Table 1, Exp 1) and partial addition (at 0 and 60 min in Exp 2) of two mol equiv. of S,S-DACH, the rheology of the reaction mixture in Exp. 2 incurred several changes. Within the first 60 min of Exp. 2, the reaction mixture transformed from yellow and fluffy (Fig. 2A) to dark green and compacted (Fig. 2B). However, scraping the green surface revealed a yellow and sticky consistency reaction mixture, suggesting the presence of unreacted S,S-DACH. Therefore, more time was required for the first mol. equiv. of S,S-DACH to be consumed prior to the addition of the second mol. equiv. (Table 2 Exp. 3). The duration of S,S-DACH consumption was determined by the observed change in the appearance of the reaction mixture (Fig. 2A–C), which occurred within 99 min.

Fig. 2 Different durations of PHENSS reaction mixture where A: step 1, 0 min post milling; B: step 1, 30 min post milling; C: step 1, 99 min post milling (prior to the addition of the 2nd mol. equiv. of S,S-DACH); D: step 2, 40 min post milling; E: step 2, 80 min post milling (final product).

Table 2 Reaction duration, purity, yield and solubility of PHENSS, 56MESS, 47MESS, 4MESS, 3478MESS and 5ClSS synthesised using mechanochemistry

Complex	Reaction time (h)	Product peak area 254 nm pre-purification (%)	HPLC 254 nm (purity%)	Yield (%)	Solubility in H2O (μL mg^−1)
PHENSS	3	98.0	100.0	89	12.9
PHENSS (up-scaled reaction)	4.5	99.4	100.0	88	12.9
56MESS	3	94.1	97.2	89	12.3
47MESS	7	95.9	97.2	80	18.8
4MESS	6	96.8	97.6	82	6.7
3478MESS	5	87.1	93.1	70	37.8
5ClSS	3	94.1	97.5	72	10.0

---

Manually scraping the reaction mixture from the walls of the reaction vessel followed by a short manual kneading with a spatula is necessary to ensure consistency, higher yields and reduction in reaction times throughout our experiments. To further optimise the developed method and avoid the need for manual scraping and kneading, LAG using H₂O as a solvent was explored. Unfortunately, despite adding 100 μL of H₂O following previously reported LAG methodologies,³⁶ the reaction did not reach completion within the expected 3 h of milling. In fact, additional S,S-DACH was required to achieve full conversion, suggesting potential amine breakdown due to the presence of H₂O. Consequently, LAG was discontinued, and a small amount of sodium chloride was added to prevent reaction mixture clumping to obtain more effective milling, thus avoiding the need for manual mixing. Unfortunately, this adjustment did not produce any improvement in the reaction outcome.

Further experimental conditions were tested to investigate whether the gradual addition of S,S-DACH is still necessary when manual mixing is applied (Table 1 Exp. 4). This experiment confirmed that the developed “milling and kneading” mechanochemical method, denoted in Exp. 3 and Scheme 1, remain the most effective.

The mechanochemical synthesis of PHENSS provides significant advantages over the traditional in-solution method. Although the mechanochemical approach requires a larger quantity of S,S-DACH, this is far outweighed by the substantial reduction in reaction time and solvent use, while affording a high yield. Furthermore, PHENSS synthesis was successfully scaled up from 0.15 g to 1 g of [Pt(Phen)Cl₂]. The larger-scale reaction mimicked the smaller-scale results, reaching completion in just 4.5 h with comparable yield (88%) and purity (100%). In contrast, scaling up via the conventional in-solution method results in a reduced yield and a longer reaction time. In solution, to obtain gram/multigram scales, multiple small-scale reflux reactions can be performed. However, this approach drastically increases workload and solvent use, further highlighting the highly efficient mechanochemical approach developed.

To investigate the applicability of the optimised mechanochemical method, additional Pt(II) complexes with Phen derivatives were successfully synthesised (Fig. 3 and Table 2). All complexes were produced with high yields and purity, consistent with published values.^12,37,38 Methylated derivatives, particularly those substituted at the 3, 4, 7, and 8 positions, required longer reaction durations and slightly lower yields, likely due to steric effects. Our observations demonstrate the applicability and sustainability of this new synthetic method. Although the Pt(II) complexes in Table 2 can be synthesised in solution, mechanochemistry offers quicker access to large quantities of potent anticancer metal coordination complexes, appealing to pharmaceutical companies looking to streamline their processes.

Fig. 3 Chemical structures of PHENSS, 56MESS, 47MESS, 4MESS, 3487MESS and 5ClSS.

Optimised purification and characterisation of [Pt(S,S-DACH)(P_L)Cl₂]

The current published solution-based method employs a C18 reverse-phase Sep-Pak column to purify these Pt(II) complexes,¹⁰ which presents significant environmental and practical drawbacks. For instance, for a typical 0.1–1 g scale reaction, a minimum of 40 min is required to run a Sep-Pak column using BIO-RAD UV monitor and Econo pump. Additionally, a high volume of solvents is required to prepare, operate and wash a Sep-Pak column throughout the purification step. As the batch size increases so does the time and solvent volume required for purification.

To address this, we developed an alternative method whereby PHENSS was precipitated by dissolving the crude reaction in minimal H₂O (in accordance with PHENSS solubility shown in Table 2), syringe filtering to remove unreacted [Pt(Phen)Cl₂], and adding acetone to isolate the product from excess S,S-DACH. The precipitate was then collected through vacuum filtration, dissolved in minimal H₂O and lyophilised until completely dry to prevent the product from darkening over time, which indicates a possible Pt(II) breakdown. This method achieved 85–90% yield and was effective for PHENSS.

Other complexes such as the 5ClSS, can also be successfully isolated using this approach with consistent yields of 70–80%. However, methylated derivatives showed lower yields, speculated to be attributed to their increased solubility in acetone and residual S,S-DACH. To counteract the effect of residual S,S-DACH, a mild base (i.e., caesium carbonate) was added prior to acetone to react with free S,S-DACH. Despite the isolated target complex being pure using this approach, the presence of the mild base causes the breakdown of the Pt(II) complex (see inset in Fig. 4). Therefore, tetrahydrofuran (THF) was used as an alternate precipitant which improved the yields for these derivatives. This alternate method significantly reduced cost, purification time and solvent use, in comparison to the conventional column methodology. However, THF is classified as problematic under the CHEM21 guide.³⁹ Although the experiments conducted in this work used small amounts of THF (50 mL) and were performed with care, ongoing efforts are focused on identifying greener solvent alternatives such as 2-methyltetrahydrofuran (2-MeTHF), particularly for up-scaled reactions.

Fig. 4 ¹H NMR of 56MESS purification with caesium carbonate. Inset: 1D ¹⁹⁵Pt NMR after purification, showing the expected Pt shift for 56MESS, and decomposed NMR sample over time.

HPLC confirmed purities exceeding 90% for all Pt(II) complexes, consistent with published values.^12,37,38 Structural integrity as well as purity were verified by ¹H, COSY, ¹³C, and ¹⁹⁵Pt NMR, some ¹³C spectra have not been previously published. ESI-MS provided additional confirmation through expected mass peaks and isotopic distributions. CD spectra demonstrated retention of chirality, with characteristic absorption bands matching uncoordinated S,S-DACH.⁴⁰ The molar extinction coefficient (ε) and the standard errors for each complex were obtained via UV-Vis experiments and were calculated using the plot of the absorbance versus concentration as well as the Beer–Lambert Law equation. While elemental microanalysis showed the expected elemental composition of all complexes.

Direct comparison of the in vitro activity of Pt(II) complexes synthesised via mechanochemistry and in solution

Comparing the in vitro activity of biologically active complexes synthesised via mechanochemistry to the activity of the same complexes obtained by traditional methods is essential and highly relevant insight into the broader implementation of mechanochemical methodologies in pharmaceutical development. Given the scarcity of studies offering such direct comparisons,⁴¹ we evaluated the growth inhibition (GI₅₀ values) of our Pt(II) complexes prepared through both in solution and mechanochemistry. These complexes were tested in 12 different cell lines. For the in-solution dataset, the GI₅₀ values of only a few complexes have previously been published following the same in vitro method described in this work.⁴⁰

The GI₅₀ results of the six Pt(II) complexes synthesised using the mill showed trends and magnitudes comparable to the values obtained from the in-solution method and were also consistent with values reported in the literature (Fig. 5), as would have been expected.⁴⁰ Among the 144 data points collected, only a few discrepancies were observed between the two methods. PHENSS synthesised mechanochemically showed lower GI₅₀ values, 0.30 ± 0.07 μM in the breast (MCF-7) and 0.49 ± 0.02 μM in the skin (A431) cell lines, compared to the PHENSS obtained in solution, which showed values of 1.20 ± 0.57 μM and 1.05 ± 0.26 μM, respectively. Conversely, complexes synthesised in solution including PHENSS showed lower GI₅₀ values in other cell lines like colon (HT29) (see ESI†). Given the lack of a consistent trend in these minor differences, the variation is likely not method-dependent but rather attributed to biological factors inherent to the use of cell line cultures. Overall, this analysis confirms that the in vitro activity of these complexes was not adversely affected by mechanochemistry. The full GI₅₀ dataset and related graphs are provided in the ESI.†

Fig. 5 Selected cell lines displaying similar growth inhibition (GI₅₀, MTT assay) trends between Pt(II) complexes synthesised via mechanochemistry and in solution. Mechanochemical synthesis is denoted by the green bars whereas complexes made in solution are represented by the red bars. GI₅₀ μM is the concentration that induces 50% growth inhibition after 72 h exposure compared with untreated controls. The lower the value, the greater the growth inhibition.

Green metric calculations for mechanochemistry vs. in-solution syntheses of PHENSS

Environmental footprint and sustainability of chemical processes have become increasingly important over the last decade.^42–44 However, direct comparisons between mechanochemical and conventional solution-based methodologies are still scarce for the synthesis of metal complexes and rare for biologically active metal-containing species.^45–48 Therefore, we compared our approach to the previously reported solution-based method.¹⁰

Qualitatively, a side-by-side comparison of the different steps required for the synthesis of the Pt(II) metal complexes indicates several advantages (less complexity, fewer hazards, shorter times, less waste management) for the mechanochemical route to obtain comparable or better yields.

For a quantitative comparison, a green chemistry metrics (GCM)⁴⁹ approach was used for comparison. Same-scale PHENSS reactions, using 0.15 g of [Pt(Phen)Cl₂] (mechanochemistry) and [Pt(S,S-DACH)Cl₂] (in solution) as starting materials, were evaluated in terms of yields, reaction duration, volume of solvent used, cost of reagents and energy consumption prior to purification. The energy consumption was calculated using an example found in the literature.⁴⁶ The cost of PHENSS synthesised by each method was calculated based on the best prices of reagents purchased by our research group, along with the estimated cost of energy. In addition, the environmental factor (E-factor),³⁷ atom economy (AE), process mass intensity (PMI), and reaction mass efficiency (RME) for both synthetic routes were also calculated. All calculations are available in the ESI.†

The mechanochemical synthesis of PHENSS exhibited superior efficiency compared to the conventional in-solution method (Fig. 6). Mechanochemistry reduced reaction time by 8-fold and energy consumption by 28.8-fold, whilst producing similar yields (89 vs. 79%, respectively). Although solvent use was eliminated during the mechanochemical process, the 14 mL of solvent accounts for the in-solution preparation of the precursor [Pt(Phen)Cl₂], which will be addressed in future work. Nevertheless, in-solution synthesis still required 3.6 times more solvent than the mechanochemical process. The use of a large volume of H₂O in the in-solution synthesis led to considerable increase in both the E-factor and PMI values shown in Fig. 6. In contrast, the mechanochemical process resulted in a dramatic reduction of about 700-fold in the E-factor and 200-fold in the PMI by eliminating solvent.

Fig. 6 Cluster bar graph comparing same-scale mechanochemistry and in-solution reaction parameters and green metrics of PHENSS prior to purification.

In terms of cost and RME, both methods were comparable, with a slightly better AE for the in-solution method due to excess S,S-DACH requirement for the mechanochemical route (see ESI†). Nevertheless, based on all the examined experimental parameters and green metric values, mechanochemistry surpasses the in-solution synthesis of PHENSS in terms of sustainability, efficiency and economically.

Conclusions

This study successfully demonstrates the feasibility of synthesising Pt(II) heteroleptic complexes using mechanochemistry, offering a scalable and efficient alternative to the traditional in-solution method. PHENSS, 56MESS, 47MESS, 4MESS, 3478MESS and 5ClSS were successfully obtained with high yields and purity using an unconventional milling and kneading approach. HPLC, NMR, UV-Vis, CD, ESI-MS and elemental microanalysis, provided evidence of the structural integrity and purity of all synthesised Pt(II) complexes, which were in alignment with the published literature.

PHENSS was used as an exemplar to show that the mechanochemical process is not only easily scalable but also leads to a significant reduction in reaction time, solvent use and energy consumption with comparable cost of synthesis. Furthermore, green metric analysis using PHENSS showed a significant reduction of about 700-fold in the E-factor and ∼200-fold in the PMI. The RME was comparable for both mechanochemistry and in-solution methods, with slightly better AE for the in-solution approach. The RME and AE values reflect the need for excess S,S-DACH when mechanochemistry is applied. Currently, further optimisations are being undertaken to modulate the stoichiometric amount and further improve the RME and AE for the mechanochemistry synthesis of Pt(II) complexes. To further enhance the sustainability of the developed method, future work is focusing on synthesising the precursor [Pt(S,S-DACH)Cl₂] using mechanochemistry, aiming to achieve a completely solvent-free process. In parallel, greener solvents will be identified and evaluated as alternatives to THF for the purification step.

The determined in vitro activity of the complexes is consistent with those synthesised in solution and reported previously, confirming that mechanochemistry is a viable option for producing bioactive complexes.

Overall, our proof-of-concept findings advance the synthesis of Pt(II)-heteroleptic complexes and provide a robust framework for sustainable and scalable production of a broader range of metal coordination complexes, with wide-reaching implications for research and industrial applications. We hope this work serves as an inspiration for other medicinal chemists to expand the emerging field of inorganic medicinal mechanochemistry.

Author contributions

F. Rashid conceptualised, carried out the necessary investigations and developed the methodology for this work. The formal analysis and writing of the initial draft were also performed by F. Rashid. Dr Gordon provided guidance and assisted with writing – review and editing. Dr Sakoff and Dr Gilbert carried out the GI₅₀ investigation. Dr García contributed through supervision, conceptualisation, methodology development and writing – review and editing. Prof. Aldrich-Wright provided supervision, contributed to the conceptualisation and development of the methodology, as well as writing – review and editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

All supporting data is provided in the ESI.†

Acknowledgements

Thank you to Western Sydney University for financially supporting F. Rashid through an Australian Postgraduate Award. Thank you to the School of Science at Western Sydney University for supporting this project via Research Training Program (RTP) funding and Sustainable Development Goals grant (SDG 12 – responsible consumption and production). Additional thanks to the Nuclear Magnetic Resonance (NMR) and Electrospray Ionisation Mass Spectroscopy (ESI-MS) facilities located at Western Sydney University for providing training and access to their equipment.

References

1. F. Bray, M. Laversanne, H. Sung, J. Ferlay, R. L. Siegel, I. Soerjomataram and A. Jemal, CA-Cancer J. Clin., 2024, 74, 229–263.
2. S. Chen, Z. Cao, K. Prettner, M. Kuhn, J. Yang, L. Jiao, Z. Wang, W. Li, P. Geldsetzer, T. Bärnighausen, D. E. Bloom and C. Wang, JAMA Oncol., 2023, 9, 465–472.
3. S.-Y. Yang, Y. Chen, R. T. K. Kwok, J. W. Y. Lam and B. Z. Tang, Chem. Soc. Rev., 2024, 53, 5366–5393.
4. K. Li, G. S. Ming Tong, Q. Wan, G. Cheng, W.-Y. Tong, W.-H. Ang, W.-L. Kwong and C.-M. Che, Chem. Sci., 2016, 7, 1653–1673.
5. P. I. Ali, W. Wani, K. Saleem and A. Haque, Anti-Cancer Agents Med. Chem., 2012, 13, 296–306.
6. T. C. Johnstone, K. Suntharalingam and S. J. Lippard, Philos. Trans. R. Soc., A, 2015, 373, 20140185.
7. C. R. Brodie, J. G. Collins and J. R. Aldrich-Wright, Dalton Trans., 2004, 1145–1152,  10.1039/B316511F.
8. D. M. Fisher, R. R. Fenton and J. R. Aldrich-Wright, Chem. Commun., 2008, 5613–5615,  10.1039/B811723C.
9. A.-M. Florea and D. Büsselberg, Cancers, 2011, 3, 1351–1371.
10. N. J. Wheate, R. I. Taleb, A. M. Krause-Heuer, R. L. Cook, S. Wang, V. J. Higgins and J. R. Aldrich-Wright, Dalton Trans., 2007, 5055–5064,  10.1039/B704973K.
11. A. Khoury, J. A. Sakoff, J. Gilbert, K. F. Scott, S. Karan, C. P. Gordon and J. R. Aldrich-Wright, Pharmaceutics, 2022, 14, 787.
12. K. M. Deo, J. Sakoff, J. Gilbert, Y. Zhang and J. R. Aldrich-Wright, Dalton Trans., 2019, 48, 17228–17240.
13. A. D. Aputen, M. G. Elias, J. Gilbert, J. A. Sakoff, C. P. Gordon, K. F. Scott and J. R. Aldrich-Wright, Int. J. Mol. Sci., 2022, 23, 10471.
14. E. Petruzzella, J. P. Braude, J. R. Aldrich-Wright, V. Gandin and D. Gibson, Angew. Chem., Int. Ed., 2017, 56, 11539–11544.
15. L. Takacs, Bull. Hist. Chem., 2003, 28, 26–34.
16. L. Takacs, Chem. Soc. Rev., 2013, 42, 7649–7659.
17. J. L. Howard, Q. Cao and D. L. Browne, Chem. Sci., 2018, 9, 3080–3094.
18. J. G. Hernández and C. Bolm, J. Org. Chem., 2017, 82, 4007–4019.
19. J.-L. Do and T. Friščić, ACS Cent. Sci., 2017, 3, 13–19.
20. S. L. James, C. J. Adams, C. Bolm, D. Braga, P. Collier, T. Friščić, F. Grepioni, K. D. M. Harris, G. Hyett, W. Jones, A. Krebs, J. Mack, L. Maini, A. G. Orpen, I. P. Parkin, W. C. Shearouse, J. W. Steed and D. C. Waddell, Chem. Soc. Rev., 2012, 41, 413–447.
21. S. L. James and T. Friščić, Chem. Soc. Rev., 2013, 42, 7494–7496.
22. J. Andersen and J. Mack, Green Chem., 2018, 20, 1435–1443.
23. N. R. Rightmire and T. P. Hanusa, Dalton Trans., 2016, 45, 2352–2362.
24. M. J. Muñoz-Batista, D. Rodriguez-Padron, A. R. Puente-Santiago and R. Luque, ACS Sustainable Chem. Eng., 2018, 6, 9530–9544.
25. C. Xu, S. De, A. M. Balu, M. Ojeda and R. Luque, Chem. Commun., 2015, 51, 6698–6713.
26. A. A. Gečiauskaitė and F. García, Beilstein J. Org. Chem., 2017, 5, 2068–2077.
27. D. Tan and F. García, Chem. Soc. Rev., 2019, 48, 2274–2292.
28. A. Stolle, T. Szuppa, S. E. S. Leonhardt and B. Ondruschka, Chem. Soc. Rev., 2011, 40, 2317–2329.
29. I. E. Chikunov, G. S. Ranny, A. V. Astakhov, V. A. Tafeenko and V. M. Chernyshev, Russ. Chem. Bull., 2018, 67, 2003–2009.
30. C. J. Adams, M. Lusi, E. M. Mutambi and A. G. Orpen, Cryst. Growth Des., 2017, 17, 3151–3155.
31. V. D. P. Makhaev and A. Larisa, Molecules, 2023, 28, 3496.
32. A. Garci, K. J. Castor, J. Fakhoury, J.-L. Do, J. Di Trani, P. Chidchob, R. S. Stein, A. K. Mittermaier, T. Friščić and H. Sleiman, J. Am. Chem. Soc., 2017, 139, 16913–16922.
33. T. Seki, K. Sakurada, M. Muromoto, S. Seki and H. Ito, Chem. – Eur. J., 2016, 22, 1968–1978.
34. T. Seki, Y. Takamatsu and H. Ito, J. Am. Chem. Soc., 2016, 138, 6252–6260.
35. W. D. McFadyen, L. P. G. Wakelin, I. A. G. Roos and V. A. Leopold, J. Med. Chem., 1985, 28, 1113–1116.
36. T. Friščić, S. L. Childs, S. A. A. Rizvi and W. Jones, CrystEngComm, 2009, 11, 418–426.
37. J. Baz, A. Khoury, M. G. Elias, N. Mansour, S. Mehanna, O. Hammoud, C. P. Gordon, R. I. Taleb, J. R. Aldrich-Wright and C. F. Daher, Chem.-Biol. Interact., 2024, 388, 110834.
38. A. M. Krause-Heuer, R. Grünert, S. Kühne, M. Buczkowska, N. J. Wheate, D. D. Le Pevelen, L. R. Boag, D. M. Fisher, J. Kasparkova, J. Malina, P. J. Bednarski, V. Brabec and J. R. Aldrich-Wright, J. Med. Chem., 2009, 52, 5474–5484.
39. D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-Shehada and P. J. Dunn, Green Chem., 2016, 18, 288–296.
40. F. J. Macias, K. M. Deo, B. J. Pages, P. Wormell, J. K. Clegg, Y. Zhang, F. Li, G. Zheng, J. Sakoff, J. Gilbert and J. R. Aldrich-Wright, Chem. – Eur. J., 2015, 21, 16990–17001.
41. A. S. McCalmont, A. Ruiz, M. C. Lagunas, W. T. Al-Jamal and D. E. Crawford, ACS Sustainable Chem. Eng., 2020, 8, 15243–15249.
42. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, 2000.
43. U. Nations, Sustainable Development Goals, https://sdgs.un.org/goals, (accessed 31/03/2025).
44. A. C. Society, Chemistry and Sustainability Development Goals, https://www.acs.org/content/acs/en/sustainability/chemistry-sustainable-development-goals.html, (accessed 31/03/25).
45. N. Fantozzi, J.-N. Volle, A. Porcheddu, D. Virieux, F. García and E. Colacino, Chem. Soc. Rev., 2023, 52, 6680–6714.
46. V. K. Singh, A. Chamberlain-Clay, H. C. Ong, F. León, G. Hum, M. Y. Par, P. Daley-Dee and F. García, ACS Sustainable Chem. Eng., 2021, 9, 1152–1160.
47. F. Leon, C. Li, J. F. Reynes, V. K. Singh, X. Lian, H. C. Ong, G. Hum, H. Sun and F. García, Faraday Discuss., 2023, 241, 63–78.
48. J. A. Cabeza, J. F. Reynes, F. García, P. García-Álvarez and R. García-Soriano, Chem. Sci., 2023, 14, 12477–12483.
49. A. C. Lapkin and D. J. Constable, Green Chemistry Metrics: Measuring and Monitoring Sustainable Processes, 2008.

---

Footnote

† Electronic supplementary information (ESI) available See DOI: https://doi.org/10.1039/d5gc02781k

---